Hoarseness as the initial presentation of multiple myeloma

Key Clinical Message Myeloma of the thyroid cartilage is a rare but important differential diagnosis of a laryngeal mass. Although hoarseness as the initial presenting symptom in multiple myeloma is extremely rare, a clinician should always consider it. Abstract Multiple myeloma (MM) is a malignant plasma cell disorder characterized by an uncontrolled proliferation of monoclonal plasma cells. Although the clinical presentation at diagnosis can be quite variable, thyroid cartilage infiltration in MM is rare. Here we discuss a 65‐year‐old Caucasian male presenting to the ENT doctor with continuous hoarseness for 3 months. The initial clinical examination showed a tangible mass at the left lymph node level II–III. Further examination with fiber‐optic laryngoscopy showed a bulging of the aryepiglottic and ventricular fold. Neck and chest CT scan revealed multiple osteolytic bone lesions in addition to the large lesion in the left thyroid cartilage. Laboratory work‐up, PET‐CT scan and biopsy of the thyroid cartilage were performed and eventually all confirmed the presence of a new diagnosis of IgA kappa MM. The patient was referred to the department of hematology to start with chemotherapy.


| INTRODUCTION
Multiple myeloma (MM), a malignant plasma cell disorder of the post-germinal center B-cells in the bone marrow, is the second most common hematological malignancy in developed countries and accounts for around 1% of all cancers worldwide. [1][2][3] In almost all patients, MM initially present as monoclonal gammopathy of undetermined significance (MGUS) and is characterized by an asymptomatic, uncontrolled proliferation of monoclonal plasma cells without any evidence of end-organ damage. The plasma cells produce nonfunctional, intact immunoglobulins or immunoglobulin chains which can be detected in the serum and form the basis of the initial diagnosis. 4 Specific criteria for progression to and the diagnosis of MM are defined by the International Myeloma Working Group (IMWG) and include validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcemia, renal failure, anemia, and bone lesions). 5 In uncommon cases, the plasma cell neoplasm may arise within the soft tissues, called extramedullary plasmacytomas (EMP). 6 The clinical presentation of MM at diagnosis is in most cases quite variable and non-specific. 1 Based on a retrospective single-institution study of 1027 patients, the most common symptoms at presentation were: anemia (73%), bone pain (58%), elevated creatinine level (48%), fatigue (32%), hypercalcemia (28%), and weight loss (24%). 7 In this case report we discuss a 65-year-old Caucasian male who presented with hoarseness as the initial symptom of MM.

| CASE REPORT
A 65-year-old male presented to the ear, nose, and throat (ENT) department at the Antwerp University Hospital. The patient reported continuous hoarseness since 3 months which initially started as a tickling cough. There were no periods of complete aphonia. He also complained of sternal pain radiating to the right ribcage, triggered by coughing and sneezing. The intake of solid and liquid substances was preserved and no dysphagia for liquids or solids was reported. The patient showed no weight loss, night sweats or fever. At the time of presentation, the patient had no significant medical history or known allergies and did not take any medication. He had a history of smoking (five pack years, 40 years ago) and alcohol use was limited to two to three units per day. The hoarseness made it impossible to work as he was a professional voice user.
On the clinical examination, a tangible mass was discovered in the neck at the left lymph node level II-III. Except for distinct hoarseness, no other abnormalities were observed. To further investigate the pharynx and larynx, a fiber-optic laryngoscopy was performed. A bulging of the left aryepiglottic fold and ventricular fold was observed. Stroboscopy showed asymmetry of the vocal cords with irregular movement and suboptimal glottal closure. It is unclear whether the hoarseness is due to nerve damage or physical obstruction or a combination of both. Considering there was a subtle mass tangible at palpation and a clear bulging of the aryepiglottic and ventricular fold, a CT scan of neck and chest was performed showing diffuse osteolytic bone lesions of which some had an extraosseous extension ( Figure 1A). Furthermore, multiple lesions were found in the thyroid cartilage of which the largest lesion on the left side with extensive extraosseous extension ( Figure 1B,C).
To further examine the cause, a more extensive work-up with laboratory analysis (including protein electrophoresis and immunofixation), PET-CT scan and an ultrasound-guided Tru-Cut biopsy of the right clavicula and the left thyroid cartilage were performed. Lab results showed an M-peak of 57,3 g/L on protein electrophoresis with IgA protein level of 49.84 g/L, hypercalcemia, renal insufficiency and a mild anemia, all suggestive of MM with high tumor burden (Table 1).
Moreover, PET-CT scan demonstrated multiple intense foci in the skeleton and bilateral in the thyroid cartilage suspicious for a malignancy (Figure 2). A Tru-Cut biopsy was taken, showing diffuse tissue invasion by a plasma cell neoplasia with kappa light chain restriction, conforming the presence of IgA kappa MM (Figure 3).
Thereafter, the patient was urgently referred to the hematology department to start with chemotherapy after performing a bone marrow biopsy and additional lab analysis. The bone marrow was invaded by an atypical population of plasma cells with kappa light chain restriction, making up 60%-65% of bone marrow cellularity. Cytogenetics showed no high-risk chromosomal abnormalities and his R-ISS score 8 was stage II, due to a ß2 microglobulin level of 10,68 mg/L and serum albumin level of 34.7 g/L, which corresponds with a median progression-free survival of 42 months. However, the extramedullary nature of the disease is not taken into account in the scoring system of the R-ISS.
As the patient was transplant-eligible we started with induction chemotherapy consisting of bortezomib, cyclophosphamide and dexamethasone (VCD) once weekly, with the purpose of autologous stem cell transplantation as consolidation after four 28-day cycles of VCD. It was expected that the dysphonia would get better with treatment.

| DISCUSSION
In most patients with MM the plasma cell proliferation is restricted to the bone marrow, however a subset develops soft-tissue plasmacytomas, whereby clonal plasma cells escape and are found outside the bone marrow. 9 Hoarseness, as the initial presenting symptom in patients with MM is exceedingly rare but can be the result of EMP with involvement of the thyroid cartilage.
Only a few cases of EMP of the thyroid cartilage have been reported in the literature so far, and as with other extramedullary disease, it is associated with a poor prognosis. [10][11][12][13][14][15][16] Two possible mechanisms for thyroid cartilage involvement have been suggested: (1) Osseous metaplasia of the cartilage into bone marrow and the subsequent proliferation of plasma cells or (2) direct invasion by an adjacent soft tissue plasmacytoma into the thyroid cartilage. The exact mechanism, however, remains elusive. 10 Although the most common cause of a thyroid cartilage mass is a squamous cell carcinoma, around 80% of EMPs are also located in the head and neck region, making this an uncommon but important differential diagnosis. 16 While hoarseness as the initial presenting symptom in MM is extremely rare, a clinician should always consider it, especially in the presence of systemic symptoms like hypercalcaemia, unexplained renal insufficiency or osteolytic bone lesions.

FUNDING INFORMATION
None of the authors involved in the writing of this case report received financial support from any party in relationship to content of this manuscript that might influence the authors opinion or editorial independence in the present or recent past.